1.alpha.-Hydroxylated cholecalciferols (vitamin D.sub.3 s), particularly 1.alpha.-hydroxycholecalciferol and 1.alpha.,25-dihydroxycholecalciferol, metabolites of cholecalciferol, are more active than the vitamin in both intestinal calcium transport and bone calcium mobilization and therefore have been extensively studied for the treatment of various vitamin D.sub.3 deficiency diseases. Promising results have been obtained with 1.alpha.-hydroxylated cholecalciferols in the treatment of such diseases, for example, osteoporosis and renal failure. See the review article on vitamin D by J. L. Omdahl and H. F. DeLuca, Physiological Reviews, 53, 327 (1973).
The interesting biological activity exhibited by 1.alpha.-hydroxylated derivatives of cholecalciferol has stimulated very extensive chemical research activity directed toward the synthesis of 1.alpha.-hydroxylated cholesterols, which are readily converted to the 1.alpha.-hydroxylated cholecalciferols following well-trodden paths. See, for example, B. Pelc and E. Kodicek, J. Chem. Soc. (C), 1624 (1970), M. Morisaki, et al., Chem. Pharm. Bull. (Japan), 21, 1853 (1973), J. J. Rubio-Lightbourn, Chem. Pharm. Bull. (Japan), 21, 1854 (1973), D. H. R. Barton, et al., J. Am. Chem. Soc., 95, 2748 (1973) and D. H. R. Barton, et al., J.C.S. Chem. Comm., 203 (1974).
Recently, J. A. Iacobelli, et al., in U.S. Pat. No. 3,887,545, issued June 3, 1975, described a novel synthesis of 1.alpha.-hydroxylated cholesterols starting from the epoxyketone of formula I and involving the steps of reductively cleaving the epoxy group of I to the hydroxyketone of formula II, reducing the keto group of II to the diol of formula IV and eliminating the sulfonyloxy group of IV to the 1.alpha.-hydroxylated cholesterols of formula V. See Reaction Scheme I.
The use of difficultly preparable and potentially hazardous aluminum amalgam to reductively cleave the epoxyketone of formula I to the extremely labile .beta.-ketoalcohol of formula II in the Iacobelli scheme, while of no serious consequence when the synthesis is performed on a laboratory scale, detracts from its efficiency and practicality when the synthesis is scaled-up to, for example, pilot plant levels. Thus a synthesis of 1.alpha.-hydroxylated cholesterols avoiding the use of aluminum amalgam and the formation of the labile intermediate .beta.-ketoalcohol of formula II would be a major advance in the art of providing 1.alpha.-hydroxylated cholesterols as the ultimate precursors of 1.alpha.-hydroxylated cholecalciferols. The present invention describes such a process for the preparation of 1.alpha.-hydroxylated cholecalciferols.